Article pubs.acs.org/IECR
Continuous Polymer Coating/Encapsulation of Submicrometer Particles Using a Solid Hollow Fiber Cooling Crystallization Method Dengyue Chen, Dhananjay Singh, and Kamalesh K. Sirkar* Otto York Department of Chemical, Biological and Pharmaceutical Engineering, New Jersey Institute of Technology, University Heights, Newark, New Jersey 07102, United States
Robert Pfeffer School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, Arizona 85287, United States ABSTRACT: Currently, no technique is available to continuously film coat nanosized drug particles with a polymer to produce large amounts of free-flowing coated particles. In this work, Eudragit RL 100 and poly(D,L-lactide-co-glycolide) (PLGA) were chosen as the coating polymers and Cosmo 55 (550 nm silica particles) as a surrogate for drug particles. After determining the cloud point of the polymer solutions by UV spectrophotometry, we adopted the solid hollow fiber cooling crystallization (SHFCC) technique to continuously coat the submicrometer particles with the polymer. In this method the polymer solution containing a suspension of submicrometer particles flows in the lumen of a solid polymeric hollow fiber. Controlled cooling of the polymer solution by a coolant on the shell side of the hollow fibers allows for polymer nucleation on the surface of the particles; the precipitated polymer forms a thin film around the particles, the thickness of which can be varied depending on the operating conditions. Scanning electron microscopy, transmission electron microscopy, energy-dispersive X-ray spectrometry, laser diffraction spectroscopy, and thermogravimetric analysis were all used to characterize the coatings. The results indicate that a uniformly coated and free-flowing product can be achieved under optimized conditions in the SHFCC and suitable posttreatments. Furthermore, scale-up of the method can be easily accomplished by using a larger SHFCC module containing a much larger number of solid hollow fibers. This method is easily adaptable for coating nanosized drug particles as well.
1. INTRODUCTION Nanoparticle-based drug delivery systems are of significant interest in controlled release of drugs,1,2 in delivery of anticancer drugs and imaging agents to tumors,3 in tuberculosis treatment,4 and as nonviral gene delivery vehicles.5 Important advantages of nanoparticles in drug delivery systems4 are greater solubility, high stability, high carrier capacity, incorporation of biodegradable hydrophilic/hydrophobic substances, and different ways of administering the drug including oral, injection, and inhalation methods. These desirable properties greatly improve drug bioavailability and patient compliance by reduced drug administration frequency. In drug delivery systems, each drug has a concentration range providing optimal therapeutic effects. When the concentration falls out of this range (either higher or lower), it may cause toxic effects or become therapeutically ineffective. Therefore, it is desirable to release the drug from a polymer carrier in a sustained or a controlled manner. A polymer carrier can also provide protection for fragile drugs, e.g., proteins and peptides, from hydrolysis and degradation. Protection from stomach acids is a prime example since even small drug molecules such as erythromycin can be irritating to the gastric mucosa. Lai et al.6 recently demonstrated that nanoparticles, if sufficiently coated with a muco-inert polymer such as lower molecular weight poly(ethylene glycol) (PEG), can rapidly traverse physiological human mucus with diffusivities almost as high as those in pure water. This finding suggests that it is possible to engineer (coat) nanosized drug particles to © 2014 American Chemical Society
overcome the mucus barrier, allowing sustained drug delivery to specific cells in the body at mucosal surfaces and provide improved efficacy and reduced side effects for a wide range of therapeutics. The potential for nanoparticles to revolutionize drug delivery systems is huge. However, a number of problems need to be overcome including continuously layering and coating nanoparticles with polymeric materials to achieve time release, protecting them from stomach acids and being trapped by a mucus barrier, or preventing immune cells (macrophages) from engulfing and eliminating the nanoparticles circulating in the bloodstream.7 Nanoparticle surface coating or tailoring can also provide a variety of desirable properties in physical, optical, electronic, and chemical applications. Conventional methods for coating or encapsulating micrometer-sized particles and nanoparticles utilize dry or wet approaches. Wang et al.8 have summarized these approaches: dry methods include physical vapor deposition, plasma treatment, chemical vapor deposition, and pyrolysis of polymeric organic materials; wet methods cover sol−gel processes, emulsification, and solvent evaporation techniques. Supercritical fluid processes such as rapid expansion of supercritical solutions (RESS), supercritical anti-solvent Received: Revised: Accepted: Published: 6388
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the outer diameter (od) 575 μm. The polymeric hollow fiber is of polypropylene (PP) which has a great deal of chemical, pH, and solvent resistance. One could also employ a variety of other polymers, poly(tetrafluoroethylene) (PTFE), polyimide, and so on. Polymers PP and PTFE in hollow fiber form are particularly useful since their smooth and nonsticky surfaces do not easily allow accumulation of precipitating crystals18 as long as the liquid is flowing. The polymer used to make the hollow fiber must be totally inert in the solution environment. Further, a smooth surface is necessary to eliminate roughness elements in the wall from acting as possible nucleation sites. We allowed the solution slated for crystallization to pass through the bore (or lumen) of the solid hollow fiber and to have a coolant flow on the outside of this fiber, thereby setting up heat exchange. If we allow this fiber to be part of a cylindrical heat exchange device packed with many such solid wall hollow fibers (Figure 2), we have essentially bundled together many long microfluidic channels in one small device; however, the channels are circular and the channel dimensions are considerably, almost by an order of magnitude, larger than conventional microfluidic channels. Zarkadas and Sirkar19 have experimentally demonstrated that such a 30 cm long polymeric hollow fiber heat exchanger (PHFHE) is highly efficient compared to other heat exchangers due to the very large heat exchange surface area/volume (1400 m−1) created by the polymeric hollow fiber surface area. Larger heat exchangers have been successfully tested in systems with precipitating salts of CaSO4 and CaCO3.20 For cooling crystallization from a solution flowing through the hollow fiber bore with the coolant flowing on the shell side, the SHFCC was highly efficient for both aqueous and organic crystallizing solutions.17 Examples illustrated include the following: crystallizing KNO3 from an aqueous solution,17 salicyclic acid from ethanol,17 and paracetamol from an aqueous solution.21 The number of crystals generated per unit volume was 2−3 orders of magnitude higher, CSDs were much narrower, and the mean crystal sizes were 3−4 times smaller than those from conventional mixed suspension, mixed product removal (MSMPR) crystallizers.17 The very low temperature difference between the SHFCC fiber wall and the crystallizing solution (∼1−2 °C) provided a far greater control over the nucleation/crystal growth process compared to that in a MSMPR crystallizer.17 It is equally valid when one compares the conditions in the bore of a hollow fiber to that in a metallic tube in a conventional shell-and-tube heat exchanger. In a PHFHE performing as a SHFCC, each hollow fiber acts as a separate crystallizer. It is as if the feed solution has been subdivided into numerous identical fluid packets traveling through each hollow fiber bore with the same velocity and under the same cooling conditions created by the flowing shell side cooling fluid. Therefore, the scale-up problem is minimized which is a major strength of SHFCC devices.17,19 If a few hollow fibers get accidentally blocked, the disturbance to the rest of the fiber assembly is minimal since, in a 2.54 cm diameter module, there may be as many as 90 hollow fibers; in a 5.08 cm diameter module, there will be 360 fibers. Note that the fiber bore side flow Reynolds number is quite low ( 80% as clear. 2.5. Characterization of Submicrometer Particles. Due to the limitation of resolution of a scanning electron microscope (SEM), we used relatively large 550 nm diameter COSMO 55 (JGC Catalysts and Chemicals Ltd., Somerset, NJ, USA) nonporous spherical hydrophilic silica submicrometer particles to act as the initial surrogate drug particles in the experiments reported here. A scanning electron microscope (LEO 1530 Gemini, Zeiss, Thornwood, NY, USA) was employed for simple morphological observations. Dry coated particles were attached on the top of the pin stub mount. To examine the coating covering the submicrometer particles, it is necessary to coat this sample with carbon to make the sample conductive enough to get a clear surface structure picture since charging may occur when the specimen has poor electrical conductivity, causing distorted or deformed pictures. A 200 kV Schottky field emission (JEOL JEM-2010F, Peabody, MA, USA) analytical transmission electron microscope (TEM) was used for a more thorough analysis of the samples. Z contrast related high-angle dark field images of the coated silica spheres were collected under scanning transmission electron microscopy (STEM) mode to visualize the coating surrounding each individual sphere. The probe size of the electron beam is 1 nm so an accurate thickness can be determined from the STEM image directly. Energy-dispersive X-ray spectroscopy (Model 7246, Oxford Instruments, Concord, MA, USA) provided the distribution of the elements on the surface of the nanoparticles. A thermogravimetric analyzer (Pyris 1, PerkinElmer, Waltham, MA, USA) was used to determine the amount of coating on the sample particles so that the coating thickness can be calculated by weight loss during heating. Laser diffraction spectroscopy (Vibri, Sympatec, Clausthal-Zellerfeld, Germany) was used to analyze particle size distribution and any agglomeration.
3. RESULTS AND DISCUSSION We first consider the results of cloud point studies for a number of binary and ternary systems. Then we focus on various pretreatments and posttreatments of the particle coating 6392
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system. Finally we provide detailed characterization of the coated particles. 3.1. Cloud Point for the Polymer/Solvent Binary System. The concentration vs absorbance data for the acetone solution of Eudragit RL 100 at 25 °C are shown in Figure 4.
Figure 4. Concentration vs absorbance for Eudragit RL 100 with acetone at 25 °C.
The cloud point data for PLGA/dioxane (not shown) are similar to those for Eudragit RL 100/acetone in that the transmissivity of both solutions is around 100%; the solution remains clear with no precipitation-based particles appearing with a variation in temperature. That is because the cloud point temperature for both of these polymers dissolved in a pure solvent is very low; therefore it is difficult to have precipitation due to a temperature drop under mild conditions (0−50 °C). It has been suggested23 that when dissolving PLGA/Eudragit RL 100 into dioxane/acetone, addition of a little water decreases the solvation power of the solvent. The solution will turn from clear to cloudy depending on the temperature change. Therefore we can also adjust the cloud point of the system by adjusting the amount of water added. 3.2. Cloud Point for the Polymer/Solvent/Water Ternary System. A limited amount of antisolvent such as DI water was added to the solution containing Eudragit RL 100 to increase the cloud point temperature at the same polymer concentration. At the same cloud point temperature compared to the solution without addition of water, less polymer will be in solution if a little DI water has been added; further the solution viscosity will be lower making it easier to flow. A few different concentrations of water in the ternary system of polymer/solvent/water have been tested under different temperatures. The results are provided below for the two polymers studied. 3.2.1. Eudragit RL 100. Different concentrations of Eudragit and the amount of water added in a Eudragit/acetone/water ternary system have been studied under different temperatures. Parts a and b of Figure 5 illustrate the behavior of one such solution; Table 2 provides a summary of the cloud point temperatures observed for three different compositions of acetone/water. Since 15 °C is a modest temperature and was easy to achieve, a ratio of 2.5/0.5 for acetone/water was selected to obtain the transmissivity vs wavelength plot at a few temperatures as shown in Figure 5a; Figure 5b illustrates how transmissivity decreases with temperature for a few wavelengths. 3.2.2. PLGA. Different concentrations of PLGA and the amount of water added in the ternary system of PLGA/
Figure 5. (a) Transmissivity of a 10 wt % Eudragit RL100/(2.5 mL of acetone)/(0.5 mL of water) solution vs wavelength at different temperatures. (b) Transmissivity of a 10 wt % Eudragit RL100/(2.5 mL of acetone)/(0.5 mL of water) solution vs temperature for a few wavelengths.
Table 2. Cloud Point Temperatures vs Different Ratios of Acetone/Water in Eudragit RL100 Solution ratio of acetone/water (mL/ mL)
cloud point temp of 10 wt % Eudragit RL100 (°C)
2.5/0.5 2.5/0.52 2.5/0.54
15 20 30
dioxane/water have also been tested under different temperatures. Compared to experiments with Eudragit, the change from clear to cloudy status is easier to see through visual observations or transmissivity in UV. Figure 6 provides a graphical summary of cloud point temperature vs the ratio of dioxane/water for PLGA. A ratio of 2.5/0.5 (dioxane/water) for 10 wt % PLGA solution or 2.5/ 0.56 for 5 wt % PLGA solution can be chosen for these experiments since a temperature around 20 °C is a modest temperature and easy to achieve. 3.3. Variations in Feed Solution Conditions (Pretreatments). By adjusting the feed solution conditions, such as adding different amounts of water, different amounts of silica, adding a surfactant, and changing the residence time, the coating results are seen to be very different. As already pointed out, the cloud point temperature of the two polymer solutions will change from clear to cloudy at higher (therefore more easily realizable) temperatures when adding different amounts of water. Therefore for both polymer solutions, a small amount of nonsolvent (water) was added. Particle agglomeration can be reduced by the addition of a surfactant, sodium dodecyl sulfate, to the polymer solution. 6393
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those obtained from the TGA. In our experiments when the amount of silica particles added was over 1.6 g/(20 mL of acetone), there was a tendency for clogging. The residence time is also critical for submicrometer particle coating; a longer residence time will lead to more polymer precipitation and a thicker coating. Variation of residence time can be achieved by changing the feed solution flow rate into the SHFCC. Figure 9 shows TGA and EDS results corresponding to flow rates of 1, 5, and 10 mL/min, respectively; these flow rates correspond to residence times of 76.2, 15.2, and 7.62 s, respectively. The TGA results show that as the flow rate increases, the weight loss percent decreases which indicates that the coating thickness decreases when the residence time decreases. EDS results support the same conclusion. Figure 10 shows SEM micrographs of coated particles for two different feed flow rates shown in Figure 9. Polymer coating on the submicrometer particles is seen to be less thick when the flow rate is increased, i.e., residence time is lowered; agglomeration between the particles also appears to decrease as the feed solution flow rate increases. It is worth noting that the outlet temperatures for the different flow rates studied were only slightly different. We do not expect that there would be a substantial effect of the very minor difference in outlet temperature on the coating since the temperature is very low around 4 °C. 3.4. Methods for Recovering Particles (Posttreatment). A number of posttreatment strategies were explored including improved vacuum filtration speed, sonication after filtration, and centrifugation. We consider them one by one below. The thickness of the coating on the particles was reduced by incorporating a vacuum filtration device that can increase the filtration rate. Using this filtration device, the filtration rate was increased substantially by enhancing the vacuum level from 1 to 5 in. Hg and up to 16 in. Hg so that the excess polymer solution would not stay in contact with the particles to form a thicker coating. This is significant since in our experiments the duration of vacuum-driven filtration for example at 1 in. Hg was 8 min whereas that for 16 in. Hg was 5 min. The results of the enhanced vacuum filtration are shown in Figure 11 and Table 3. The SEM, TGA, and EDS studies all indicate that the faster the filtration rate is, the thinner the coating. Particle agglomeration is also much less because the polymer solution remaining on the filter paper is extracted before it can form an additional
Figure 6. Cloud point temperatures vs different ratios of dioxane/ water in PLGA solutions.
SEM photographs of coated particles with or without the addition of surfactant are shown in Figure 7. With the addition of surfactant (Figure 7b), the dispersion of the coated particles is much better as compared to those without the surfactant (Figure 7a). The critical micelle concentration (cmc) of sodium dodecyl sulfate in pure water at 25 °C is 0.0082 M; therefore the concentration of SDS cannot be too high to prevent formation of micelles which can accelerate agglomeration. Figure 8 shows the weight loss (percentage) of the coated particles obtained from thermogravimetric analysis (TGA) experiments using different amounts of silica added to Eudragit RL 100 solution. This figure also shows EDS results based on the percent of carbon which was present on the coatings. The TGA results indicate that, with more silica added to the solution, the weight loss percent is less which implies that the coating thickness around the particles is lower (more details on the TGA technique are provided in section 3.5). When the amount of silica added exceeds a certain level (over 0.8 g), the coating thickness no longer decreases and remains relatively constant. Thus, both a too low or too high silica concentration is undesirable. Too low a concentration will make the coating thickness on individual particles larger; too high a concentration will have little effect on the coating thickness, increase the pressure drop, and could result in the possibility of clogging the lumen of hollow fibers. As seen in Figure 8, the EDS results reinforce
Figure 7. SEM photographs of coated particles: (a) without surfactant; (b) with surfactant (surfactant concentration, 0.0035 M). 6394
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Figure 8. TGA and EDS results for different amounts of silica addition.
Figure 9. TGA and EDS results for coated submicrometer particles for different residence times.
Figure 10. SEM photographs of coated particles for different feed flow rates: (a) 1 mL/min and (b) 10 mL/min.
coating on the surface of the particles or liquid bridges between the particles which will lead to agglomeration. Since the filtration rate was found to be critical, all subsequent experiments were run at the highest filtration rate (16 in. Hg). Section 2.3 (Experimental Methods) discussed the use of posttreatment sonication after both filtration and centrifugation as a means of producing free-flowing particles. Experimental results of Eudragit RL 100 coated particles obtained using sonication after fast filtration are shown in Figure 12 and compared to those without the sonication posttreatment. There
is almost no excess polymer on the particles in Figure 12b compared with those in Figure 12a and agglomeration between particles is less than that in Figure 12a. By using this posttreatment method, the products were free-flowing rather than cohesive due to particles sticking together. We have also used sonication as a posttreatment after centrifugation. Similar to the results obtained by adding sonication after filtration, free-flowing particles were also obtained by adding sonication as a posttreatment after centrifugation. 6395
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Figure 11. SEM photographs of coated particles at different filtration rates: (a) slow, 1 in. Hg; (b) fast, 16 in. Hg.
governing the relation between the mass of the polymer and the mass of the particles is
Table 3. TGA and EDS Results for Coated Submicrometer Particles under Slow and Fast Filtration Conditions vacuum level
1 in. Hg
16 in. Hg
TGA weight loss (%) EDS carbon (%)
44.9 37.0
17.8 31.2
msilica = mpolymer
4 π {(r 3
4 3 πr ρsilica 3 3 3
+ h) − r }ρpolymer
(1)
The coating thickness h can be calculated as h = r(1 + ρsilica mpolymer /ρpolymer msilica )1/3 − r
3.5. Thermogravimetric Analysis of the Particles. Thermogravimetric analysis allows measurement of the change in particle mass as a function of time by increasing the temperature of the sample continuously. Samples of dry, coated particles and dry, uncoated Cosmo 55 silica particles were analyzed by TGA. The temperature in the TGA was increased at a rate of 10 °C/min until it reached 550 °C. During this period, Eudragit RL 100 polymer coating decomposed as a result of heating while the mass of the uncoated silica remained almost unchanged, as seen in Figure 13.The solid line shows that the weight percent of the coated particles was reduced from 100% to 85%, which means that the 15% weight loss was due to decomposition of the polymer coated on the particles during heating. To estimate the thickness of the coating,8 we assume that the polymer is evenly coated on the spherical submicrometer particles of radius r and forms a uniform layer. The equation
(2)
where msilica and mpolymer are the masses of the particles and polymer, respectively. The densities of the host particles and polymer are ρsliica (2.65 g/mL) and ρpolymer (1.1 g/mL), respectively. Using the results from the TGA, the coating thickness for the submicrometer particles under optimized conditions is about 33 nm. 3.6. Scale-Up Using a Larger SHFCC Module. Scale-up can be achieved by simply using a larger module containing for example double the number of hollow fibers, 46 instead of 23 (see Table 1). The 25 mm diameter filter paper used with the smaller module was replaced by a 90 mm diameter filter paper so as to be able to handle a larger amount of product. Since the number of fibers inside the SHFCC module was doubled, the flow rate was also doubled without affecting the residence time; i.e., the velocity in each hollow fiber remains the same.
Figure 12. SEM photographs of Eudragit RL 100 coated particles without posttreatment after filtration (a) and with posttreatment after filtration (b). 6396
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Figure 13. TGA micrographs of uncoated and Eudragit coated submicrometer silica particles subjected to posttreatment methods after filtration.
Figure 14. Particle size distribution for uncoated and Eudragit coated submicrometer particles from both the small and large modules.
module, and Eudragit coated particles from the large module. Table 4 shows that the Sauter mean diameter (Ds) of the 3
Therefore the larger module should produce particles having a coating similar to that from the smaller module. Coated particles collected from both modules, large and small (all other conditions are the same: 0.4 g silica; 16 in. Hg filtration speed), were characterized by TGA. The coating thickness of the particles calculated from TGA results was 33.1 nm for the large module and 33.3 nm for the small module. It should be noted that the coating thickness calculated from the TGA is an idealized value that assumes the coating on the particles to be perfectly uniform with no excess coating between the silica particles. 3.7. Laser Diffraction Spectroscopy. Sympatec laser diffraction spectroscopy (LDS) coupled with RODOS dry dispersion and R1 lens (0.1−35 μm) was used to identify the particle size distribution (PSD) of the products collected; most importantly, it can identify the amount of agglomeration present in the coated particles. A dry powder of particles coated in the small module was tested under different pressures (0.5−3 bar) to determine the average particle size. With an increase of the pressure, the powder exhibited a reduction in particle size until a plateau was observed. After the pressure reached 3 bar, the particle size did not decrease as the pressure was increased; this means that complete dispersal was achieved. Therefore the default primary pressure (Pprimary) was set as 3 bar when measuring the PSD of the samples in Figure 14. The LDS analyzer was used to measure the PSD of uncoated Cosmo 55 silica, Eudragit coated particles from the small
Table 4. Particle Size for Uncoated and Coated Submicrometer Particles Sauter mean diam (μm) uncoated particles coated particles with small module coated particles with large module
0.64 1.31 1.25
samples are 640, 1310, and 1250 nm, respectively. This indicates that the coated particles were somewhat agglomerated, forming mostly doublets and perhaps some triplets. After scale-up, the mean size of the coated particles from the large module is similar to that from the small module. However, there appears to be some difference in the extent of agglomeration of the coated particles obtained from the smaller module and the larger module (Figure 14). The coated particles go through a number of posttreatment steps after discharge from the SHFCC device. Any minor variation in these steps can contribute to the observed variation in the extent of agglomeration. 3.8. Scanning Transmission Electron Microscopy. The particle coating thickness and morphology can be much more precisely determined by TEM−STEM analysis which is used to check whether the coating thickness is in accord with the TGA results and also if it is uniform. Figure 15b shows a photograph 6397
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Figure 15. STEM micrographs of uncoated submicrometer particles (a) and coated particles under optimized condition (b).
Figure 16. EDS results of single coated submicrometer particles under optimized conditions.
of a single coated particle under optimized conditions (0.4 g of silica; 2.5 cm3/min flow rate; surfactant concentration, 0.0035 M; 4 mL of water added to 20 mL of acetone; sonication posttreatment after filtration at 16 in. Hg filtration rate; small module). The bright area is the silica particle, and the transparent gray ring represents the polymer coating. From this figure, it is easy to see that a uniform, thin coating is covering the particle, while for an uncoated silica particle shown in Figure 15a no transparent ring is seen. Based on the scale bar, the thickness of the coating around the single submicrometer particle can be estimated to be about 25 nm. Figure 16 shows the signal profile of various elements (carbon, silicon, and oxygen) in the coated silica particle shown in Figure 15b. The probe detects various elements in the particle from the surface to the interior. The point at 0.022 μm in the x-axis is the surface point of the coating; the point at 0.05 μm is the coating end point and the beginning of the surface of
the silica particle. The coating thickness can then be estimated as 0.028 μm or 28 nm. 3.9. PLGA Coated Submicrometer Particles. Coating the silica particles with PLGA was also studied in the SHFCC device but not as extensively as with Eudragit. Therefore we only show one figure which indicates that PLGA can also be coated onto the silica particles in the SHFCC device. Figure 17a shows an SEM image of silica particles in a dioxane solution of PLGA before precipitation; Figure 17b shows a SEM image of coated particles after the solution was passed through the SHFCC and precipitation has occurred. Clearly there is no coating in Figure 17a; however Figure 17b shows a uniform polymer coating covering the particles. This result is in accord with the EDS result that shows a carbon percent of 21.6 after posttreatment using fast filtration (16 in. Hg), confirming that PLGA can also be used to coat the particles by the SHFCC method. It appears that the coating 6398
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Figure 17. SEM photographs of solutions with PLGA and submicrometer particles before passing through the SHFCC (a) and after precipitation in the SHFCC (b).
polymer solution was determined by UV spectrophotometry for the polymer/solvent/nonsolvent systems of Eudragit RL100/acetone/water and PLGA/dioxane/water. The cloud point temperature of these systems was in the range of 15−25 °C. Pretreatment conditions employed include adding suitable amounts of a nonsolvent (water) and surfactant (sodium dodecyl sulfate), varying the ratio of silica to polymer, and changing the flow rate (residence time) of the submicrometer particle containing solution. Posttreatment methods for treating the coated particles such as very rapid filtration, centrifugation, and sonication were developed to control the thickness of the coating and the free-flowability (nonagglomeration) of the coated particles. This novel crystallization/coating method should be attractive for polymer coating of nanopharmaceuticals since scale-up is relatively simple and coated particles can be mass produced continuously. This is contrast to the batch nature of most coating techniques explored so far. It should be usable for most polymers and not just limited to the two polymers used here. The submicrometer silica particles used here were spherical. Drug particles and nanopharmaceuticals are likely to have a variety of shapes. It would be of interest to determine whether that would introduce any complications in developing a reasonable coating.
method developed is quite general and may be used with a variety of polymers; PLGA being biodegradable is an especially useful example since it is widely used in the pharmaceutical industry. 3.10. Effect of Operating Parameters. We will briefly summarize here the effects of various operating parameters in this technique one by one. 3.10.1. Residence Time. The residence time in the hollow fiber device containing a certain number of hollow fibers having a certain i.d. and length is determined by the volumetric flow rate of the coating suspension; the higher the volumetric flow rate, the shorter is the residence time. We have found from TGA and EDS measurements that a longer residence time will lead to a higher amount of polymer precipitation as well as enhanced bridges between neighboring coated silica particles and agglomerates. 3.10.2. Lumen-Side Exit Temperature. Other conditions remaining constant, the lumen-side exit temperature is controlled by the inlet temperature of the cooling liquid on the shell side. A lower temperature will lead to higher precipitation and thicker coating. 3.10.3. Polymer Concentration. Higher polymer concentration will tend to enhance the coating thickness and the extent of bridging between neighboring particles and agglomerates. However, a higher concentration will also have other deleterious effects: there will be higher polymer loss in the exiting solution and increased solution viscosity which will affect the processing capacity; the chances of clogging of the hollow fiber bore will increase. 3.10.4. Posttreatment Time. Among the various posttreatment steps, the collection time, the filtration time, and the centrifugation time are important in the sense that the coated submicrometer particles are in contact with a solution containing the polymer which is precipitating. Therefore it is important to reduce the duration of various posttreatment steps, especially when we have a volatile solvent, namely, acetone, which will continue to evaporate and increase the polymer concentration in solution.
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AUTHOR INFORMATION
Corresponding Author
*Tel.: 973-596-8447. Fax: 973-642-4854. E-mail: sirkar@njit. edu. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We gratefully acknowledge support for this research from the National Science Foundation through Grant CMMI-1100622. We thank the Bristol-Myers Squib Corp. (BMS), and especially Dr. San Kiang of BMS, for providing us with an industrial perspective. We also want to acknowledge and thank Dr. Jiangtao Zhu of Arizona State University for running and interpreting the TEM-Stem images of our samples.
4. CONCLUDING REMARKS A novel SHFCC crystallizer/heat exchanger was utilized to continuously coat surrogate silica submicrometer particles with polymers from a polymer solution. The cloud point of the 6399
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(23) Hua, F. J.; Park, T. G.; Lee, D. S. A facile preparation of highly interconnected macroporous poly (D,L-lactic acid-co-glycolic acid) (PLGA) scaffolds by liquid−liquid phase separation of a PLGA− dioxane−water ternary system. Polymer 2003, 44, 1911.
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dx.doi.org/10.1021/ie403993c | Ind. Eng. Chem. Res. 2014, 53, 6388−6400
